Substituted 1, 3, 5-triazinyl-(6)-aminophenyl-arsenic compounds



Patented May 21, 1946 an smrg s rrsnr oFFicE SUBSTITUTED 1,3,5-TRIAZINYL- (6) -AMINO- PHENYL-ARSENIC COMPOUNDS Ernst A. H. Friedheim, New York, N. Y.

No Drawing. Application January 20, 1944, Serial No. 518,997

8 Claims.

This invention relates to derivatives of triazines containing arsenic, and more particularly to triazine derivatives which contain trivalent arsenic. I

In my U. S. Patent No. 2,295,574 issued on September 15, 1942, I have shown that condensation of suitable derivatives of symmetric triazine with phenyl-arsonic acid derivatives results in a new type of condensation products possessing valuable therapeutic properties in diseases caused by spirochaetes or trypanosomes, such as syphilis, and African sleeping sickness.

I'have found that new triazine derivatives contaming arsenic can be obtained by condensing derivatives of 1,3,5-triazine of the formula E i if D-C CF N alkyl-amino, and aminoacyl radicals, such as NHCOCHs and NHCOCsHs; the radicals A and B are selected from the group consisting of hydrogen, halogen, OH, O Alk., O .acyl, N02, NHz, NH Alk., N Alk.2, aminoacyl, and alkyl radicals; it is to be understood that in the appended claims the term aminoradical includes -NH2- groups as well as the above mentioned substituted amino groups, and the term hydroxy radical includes -OH radicals as well as the before mentioned substituted -OH radicals; X is a divalent group selected from the group consisting of O, S, dihalides, such as C12, 12 or Bra, and sulfur-containing radicals of the type= (S.-Rl2 wherein R is an organic radical which is capable of carrying an SH-radical. Such sulfur-containing reactants are, for example, thioglycollie acid, cysteine, or gluthathione, thiophenol. As examples of the trivalent arsenic compounds to be used according to my invention, the following may be mentioned: 4-amino-phenylarsinoxide, i-chlor-phenylarsinoxide, i-aminophenylarsindichloride, 4 amino phenylarsinsulfide, 3-amino-e-oxy-phenylarsinoxide.

The condensation products thus formed have the formula Y1 N/ 1 r w- C--NH-OH:(A. B)-As=X wherein Y and'Y are each a radical selected from the group consisting of halogen, NHz, NH Alla, N Alka, hydroxy-alkyl-amino,

NHCHzCHOI-ICI-IzOH dialkyl-amino-alkyl-amino, and amino acyl radicals; A and B are selected from the group consisting of hydrogen, halogen, OH, O A1k., O acyl, N02, NI-Iz, NH Alk., N Allie, amino-acyl. and alkyl radicals, and X is a divalent radical selected from the group consisting of O, S, dihalides, sulfur containing groups of the type=(S--R) 2, wherein R is an organic radical which is capable of carrying an SH-radical, and groups having the formula In carrying out the present invention, for example an aqueous solution containing one mol of 4-oxy-B-amino-phenyl-arsinoxide may be caused to react with a fine suspension of 1 mol of 2,4,6-trichloro-l,3,5-triazine in water at a temperature of 0 C. with the exclusion of oxygen. The resulting condensation product has the formula I I on N/, N at are Subsequently, this reaction product may be treated with a base selected from the group consisting of ammonia, alkyl amines, hydroxy-alkyl amines and dialkyl-amino-alkyl amines in order to react these substances with the Cl atoms of the triazine ring. Similar reactions may be cohol from which it may be recrystallized.

t2,2'-'4,4'-tetraamino-triazinyl obtained by using a dihalide such ass-aminophenylarsindichloride instead 01 4-oxy-3-amino- PhGDYI-BISiIIOXiGGr Instead of the latter, its derivatives or isomers, such as, for instance, 2-oxy-4-amino-phenyl-arsinoxide, or i-amino- 3-oxy-phenylarsinoxide may also be used. In carrying out these reactions, instead of the. trichloro-triazine other derivatives of l,3,5-triaz ine corresponding to the formula referred to above may also be used.

I have 'further found that the condensation products according to this invention may also be obtained by first forming a condensation prodaccess-r diamino-4-4' dioxyarsenobenzene) of the fornot of the type disclosed in my above'mentioned U. .s. Patent No. 2,295,574 from a derivative of 1,3,5-triazine and a substituted phenyl-arsonic acid, and converting the condensation product thus .obtained, into a compound containing trivalent arsenic. I have found that such conver: sion can be performed without the disintegration of the basic triazinyl-aminobenzene structure by treating the triazinyl-aminobenzene arsonic solution, in the presence of hydriodic acid, with $02, hypophosphorous acid (HaPOa) or stannous chloride, or in neutral or alkaline solution with phenyl-hydrazine or sodium hydrosulfite NazszO-i The reduction with S0: or phenylhydrazine leads to the arsinoxides, or dihalogenarsines, while the treatment with stannous chloride, hypophosphorous acid, and sodium hydrosulfite leads to the corresponding arseno-compounds.

For example, one part by weight of 2,4-diamino 1,3,5-triazinyl-(6)-[amino 3 oxy-dphenylarsonic acid Ilis dissolved at about 80 C. in 100 parts of hydrochloric acid of sp. gr. 1.19.

; To the clear, warm solution ,6 part of sodium iodide is added, and a stream of 80: gas is allowed to pass through the solution. After a few acid condensation product in hydrochloric acid I inula.

( l-NH:

. N Thiscompound is moderately soluble in dilute hydrochloric acid, and insoluble in ether and rim-t chloroform. In an entirely similar manner QA- diamino-triazinyl-(6)-[4-amino phenylarsonic acid] may be subjected to reduction by means or a solution of stannous chloride in aqueous hydrochloric acid and converted into the corresponding arseno compound, 1. e. [2,2'-4i,4'- tetraamino triazinyl (6,6')] 4.4 diaminoarsenobenzene.

minutes the solution becomes cloudy, and the hydrochloride of 2,4 diamino-1,3,5 triazinyl- (6) -oxyamino-phenyl arsindichloride separates out in crystalline form. It is soluble in ethyl al- Nil-OH:

is slightly soluble in acetone, and insoluble in chloroform, CCl4 and benzene. The corresponding arsinoxide is formed by the action of alkali, such as dilute ammonia or sodium bicarbonate on the arsindichloride.

An arseno-compound' can be obtainedby the action of stannous chloride on 2,4-diaminotriazinyl-(6)-[4-oxy 3 amino phenylarsonic acid I]. One part of the latter is suspended in parts of aqueous hydrochloric 1% of hydriodic acid. on gentle warming the substance goes slowly into solution, the reaction mixture taking a yellow color. It becomes cloudy, and on standing a yellow precipitate separates, which represents the hydrochloride of the his (6- 6')l-(3-3'- 'mula acid of 1.19 density. containing about 50% stannous chloride, and

If 1 part by weight of [2-chloro-4i-amino-1,3,5-

- triazinyl-(G)J-4-aminophenyl-arsonic acid is suspended in'about 50 parts. by weight of aqueous hydrochloric acid of 1.19 density, containing about 50% stannous chloride and 1% of hydriodic' acid and subjected to gentle warming,

the suspended substance goes into solution. On

N H-CHI N N Nix-d -NH-CH;

Other compounds according to my present .in-

vention may be obtained by applying theabove described reduction process by means oi stannous chloride, hypophosphorous acid, sodium hydrosulflte or phenylhydrazine to other arsonoanilino-triazine compounds.

A condensation product obtained from 3-chloro-4-amino-phenylarsonic acid and cyanuric chloride in the manner described in my abovementioned prior Patent-2,295,574, and corresponding to the formula I -II I (ll-( 1 C-NH-O-ABOtH,

Patent 2,295,574. Upon dissolving the condensamay be first reacted with ammonia in the manner described in said prior patent in order to replace one or both of the Cl-atoms oi the triazine rings by -NH.-.- groups, and then subjected to reduction by. means of Na2S2O4 in aqueous alkaline solution to form the corresponding -arseno-cornpound. Instead of 3-chloro-4-aminophenylarsonic acid, 6-chloro-3-amino-phenylarsonic acid may be used in this example in a substantially similar manner.

4-amino-3-methyl-phenylarsonic acid and cyanuric chloride reacted in the manner described in U. S. Patent 2,295,574, form a condensation product corresponding to the formula CHI NH-C/ -4:1 i N otnuisc l c: which can be reduced in hydrochloric acid solution by means of stannous chloride in the presence of a small amount of hydriodic acid to a compound of the formula Triamino-triazine (melamine) can be reacted with 2 chloro-i-dimethylamino phenylarsonic acid in the manner described in the U. 8. Patent tion product thus formed in dilute aqueous sodium hydroxide and treating the solution with NMSQO; a compound corresponding to theior- 5 mula OCHi N ci-t i -Nn- AsA nn-c i mn N N N 4 OCH: 10 I 01 01 is formed.

may be obtained.

Reference is made to my (ac-pending application Ser. No. d22,23t,iilcd on December Q, 19st, of which this is a continuation in part.

I claim:

1. A 1,3,5-triazine derivative of the iormula a condensation product of the formula ITKCHsh NH "Ha This condensation product may be converted by the action of hypophosphorous acid into the corresponding ammo-compound.

Condensation of -amin0-3-nitro-pheny1arsonic acid with cyanuric chloride and reduction of the condensation product thusformed by means of 811012 in hydrochloric acid in the presence of a small amount of hydroiodic acid results in a compound of the formula NH:

a-aminc-3-methoxy-phenylarsonic acid may be reacted with one mol of cyanuric chloride substantially in the manner described in theU. 8

wherein Y and Y are each a radical selected I from the group consisting of halogen, and amino- 513 radicals; it and E are selected from the group consisting of hydrogen, halogen, hydromll, alkyl, and amiumradicais.

2. A Lfifidriamne derivative 0! the formula 3. A 1,8,5-triazine derivative of the formula 4. A 1,3,5-triazine compound of the formula I NH 5. A process for the preparation of a 1,3,5-triazin compound of the formula said process comprising subjecting in aqueous solution a 1,3,5-triazine derivative of the formula N v i AsOsHi wherein Y and Y are each a radical selected from the group consisting of halogen, and amino- 7 radicals; A and B are selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, and amino-radicals, to the action of a reducing agent selected from the group consisting of such, m, and NazSzO4.

6. A process as claimed in claim 5, in which I Y t HzPOa is used as a reducing agent in the presence of hydrochloric acid and driodic acid. I

7. A process as claimed in 5, in which NazSzO is used as a reducing agent in the presence of alkali.

a small amount of hy- 8. A process as claimed in claim 5, in which Such is used as a reducing agent in the presence of hydrochloric acid and a small amount of hydriodic acid.

ERNST A. H; 

